Secondary Glomerulonephritis

Primary vs. Secondary

• IgA nephropathy

• Pauci-immune necrotizing and crescentic GN

• Anti-GBM glomerulonephritis

• Membranous glomerulopathy

• Type I MPGN

• Henoch-Schonlein purpura

• Pauci-immune small vessel vasculitis

• Goodpasture syndrome

• SLE

• Cryoglobulinemic vasculitis

Antibody-mediated GN

• 3 types– Linear glomerular IgG staining (IF) with

positive anti-GBM serology– Paucity of glomerular Ig staining (IF) with

positive ANCA serology– Glomerular immune complex localization

shown as granular staining (IF) with positive serology (a-DNA, hypocomplementemia, a-HCV, a-HBV, C3Nf, cryos, ASO, increased IgA)

Linear glomerular IgG staining (IF) with positive anti-GBM serology

• With lung hemorrhage (Goodpasture syndrome)

• Without lung hemorrhage (a-GBM glomerulonephritis)

Paucity of glomerular Ig staining (IF) with positive ANCA serology

• No systemic vasculitis (ANCA glomerulonephritis)

• Systemic vasculitis but no asthma & no granuloma (microscopic polyangiitis)

• Systemic vasculitis + granulomas but no asthma (Wegener granulomatosis)

• Systemic vasculitis + eosinophilia + asthma + granulomas (Churg-Strauss syndrome)

Glomerular immune complex localization shown as granular staining (IF) with positive

serology

• IgA but no vasculitis (IgA nephropathy)• IgA + systemic vasculitis (H-S purpura)• SLE (LN)• Acute Strep/Staph infection (Acute post-infectious GN)• Mesangiocapillary changes (Type I MPGN)• GBM dense deposits (Type II MPGN)• Sub-epithelial deposits (Membranous GN)• 20 nm fibrils (Fibrillary GN)• Other features (Other GN’s)

SLE

• Activation and clonal expansion of CD4+ T cells release of cytokines activation of autoreactive B cells, proliferation & differentiation excess of antibodies against nuclear antigens: ANA, DNA, Sm, RNA, Ro, La & others.– Immune complex deposition, complement activation

complement-mediated damage– Nuclear antigens can bind to glomerular sites

(especially subepithelial) in situ immune complex formation

• HTN, APL antibodies can potentiate glomerular and vascular lesions

Modified WHO Classification of LN

• I – normal glomeruli• II – pure mesangial alterations

– A: normal LM, mesangial deposits on IF/EM– B: mesangial hypercellularity and deposits on IF/EM

• III – focal segmental glomerulonephritis– A: w/ active necrotizing lesions– B: w/ active sclerosing lesions– C: w/ sclerosing lesions

• IV – diffuse glomerulonephritis (severe mesangial, endocapillary or mesangiocapillary proliferation and/or extensive subendothelial deposits)

– A: w/o segmental lesions– B: w/ active necrotizing lesions– C: w/ active and sclerosing lesions– D: w/ sclerosing lesions

• V – diffuse membranous glomerulonephritis– A: pure membranous GN– B: associated with II-a or II-b lesions

• VI – advanced sclerosing GN

Course and Prognosis of LN

• 129 pts with WHO class III (40%) or class IV (60%) LN between 1975-1997

• 18% M, 72% F; mean age 29 yrs; 43% white; 17% AA; 40% Hisp

• 30% pts reached endpoint (doubling of Screatinine)

– R. Graham Barr, Stephen Seliger, Gerald B. Appel, Ricardo Zuniga, Vivette D’Agati, Jane Salmon and Jai Radhakrishnan. Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity

Course and Prognosis of LN

• Multivariate analysis of predictors of progression showed:– Higher Screatinine– Heavier proteinuria– AA race– Low socioeconomic status

R. Graham Barr, Stephen Seliger, Gerald B. Appel, Ricardo Zuniga, Vivette D’Agati, Jane Salmon and Jai Radhakrishnan. Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity in NDT (2003) 18: 2039-2046

Therapy of LN

• Controversial

• Class I & II – excellent renal prognosis– Treat only extrarenal manifestations

• Class III– Severity, # of glomeruli involved, ?necrotizing

lesion(s), ?crescent(s)– Steroid-sensitive vs steroid-resistant

Therapy of LN

• Class IV– Aggressive treatment to avoid irreversible

renal damage (ESRD)

NIH Data

• Data from the NIH have shown that patients with lupus nephritis who are treated with glucocorticoids and a prolonged course of cytotoxic agents have better long-term renal function than those treated with glucocorticoids alone

• 107 patients with active lupus nephritis (median follow-up = 7 yrs)

• With oral prednisone alone, the probability of renal failure began to increase substantially after 5 yrs of observation

• Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for iv CyP plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027)

• The advantage of treatment with iv CyP over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry

• Patients treated with iv CyP have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections

• As compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with iv CyP reduces the risk of ESRD with few serious complications

Austin HA III, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986;314:614-619

Plasmapheresis ?

• The prognosis of patients with SLE who have GN, especially class III & IV is poor, despite treatment with immunosuppressive therapy

• Plasmapheresis therapy has been used, but there have been few controlled clinical observations of its efficacy

• RCT of 86 patients with severe lupus nephritis in 14 medical centers• Standard-therapy regimen of prednisone and CyP vs. standard therapy plus

plasmapheresis (PEx)– PEx 3x weekly for 4 weeks– Drug therapy was standardized, with strict adherence to nine detailed

medical-management protocols• 46 patients received standard therapy and 40 patients received standard

therapy plus PEx (mean follow-up was 136 weeks)– 6 patients in the standard-therapy group and 8 patients in the PEx group

died– ESRD developed in 8 patients in the standard-therapy group vs. 10 in the

PEx group– 30 pts reached stopping points (14 in the standard-therapy group and 16 in

the PEx group– A similar number of patients in each group had a decrease in both the

serum creatinine concentration and urinary protein excretion to approximately normal values

– Patients treated with PEx had a significantly more rapid reduction of serum concentrations of antibodies against double-stranded DNA and cryoglobulins

• CONCLUSIONS: Treatment with PEx plus a standard regimen of prednisone and cyclophosphamide therapy DOES NOT improve the clinical outcome in patients with SLE and severe LN, as compared with the standard regimen alone

Lewis EJ, Hunsicker LG, Lan S-P, Rohde RD, Lachin JM. A controlled trial of plasmapheresis therapy in severe lupus nephritis. N Engl J Med 1992;326:1373-1379

MMF ?

• The combination of cyclophosphamide and prednisolone is effective for the treatment of severe lupus nephritis but has serious adverse effects. Whether mycophenolate mofetil (MMF) can be substituted for cyclophosphamide is not known.

• 42 patients with diffuse proliferative lupus nephritis– 21 pts in Group I = Prednisolone and MMF given for 12 months

vs.– 21 pts in Group II = Prednisolone and CyP given for 6 months,

followed by prednisolone and azathioprine for 6 months• 81% of the 21 patients in Group I had a complete remission, and 14%

had a partial remission vs. 76% and 14%, respectively, of the 21 patients in Group II

• The improvements in the degree of proteinuria and the Salbumin and Screatinine concentrations were similar in the two groups

• One patient in each group discontinued treatment because of side effects.

• Infections were noted in 19% of the patients in Group I and in 33% of those in Group II (P=0.29)

• Other adverse effects occurred only in group 2; they included amenorrhea (23%), hair loss (19%), leukopenia (10%), and death (10%)

• Relapse rates were 15% and 11%, respectively• Conclusions: For the treatment of diffuse proliferative lupus nephritis,

the combination of MMF and prednisolone is as effective as a regimen of CyP and prednisolone followed by azathioprine and prednisolone

Chan TM, Li FK, Tang CSO, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N Engl J Med 2000;343:1156-1162

More data for MMF …

• 59 pts w/ LN (12 III, 46 IV, 1 V-b) all received induction therapy w/ iv CyP + steroids (up to 7 mos) followed by maintenance therapy (1-3 yrs):– Group I: quarterly iv CyP 4 died, 3 ESRD– Group II: azathioprine (1-3 mg/kg/d) 1 ESRD– Group III: MMF (500-3000 mg/d) 1 died, 1 ESRD

• Chronicity index was 1.9 points lower in the CyP group than in the MMF group (P=0.009)

• For patients with proliferative lupus nephritis, short-term therapy with iv CyP followed by maintenance therapy with MMF or azathioprine appears to be more efficacious and safer than long-term therapy with iv CyP.

Gabriel Contreras, M.D., M.P.H., Victoriano Pardo, M.D., Baudouin Leclercq, M.D., Oliver Lenz, M.D., Elaine Tozman, M.D., Patricia O’Nan, R.N., and David Roth, M.D. Sequential Therapies for Proliferative Lupus Nephritis, N Engl J Med 2004;350:971-80.

Antiphospholipid Antibody Syndrome

• Associated with– Glomerular disease– Large-vessel renal involvement– Secondary hypercoagulable state

• Dialysis patients• Kidney transplant patients

Anti-Phospholipid Antibodies

• 4 types– Antibodies causing a false-positive VDRL– Lupus anticoagulants– Anticardiolipin antibodies– Antibodies to beta-2 glycoprotein-1

Antiphospholipid Antibody Syndrome

• 30-50% of pts with APL antibodies have the primary APL syndrome (no identified autoimmune disease)– Lupus anticoagulant– Antiphospholipid antibodies

• Cardiolipin• Phosphatidylserine• Other phospholipids

– Renal involvement in up to 25% of pts with primary APL syndrome

• thrombosis of blood vessels: arterial, glomerular capillaries, venous

• Interstitial fibrosis and cortical atrophy (ischemia)• HUS-TTP

Antiphospholipid Antibody Syndrome

• ESRD on HD: 10-30% prevalence of APL antibodies

• CKD and ESRD on PD: much lower prevalence of APL antibodies

• 20-60% SLE patients with APL antibodies who received renal transplants had:– Venous thromboses (i.e. DVT)– PE– Persistent thrombocytopenia

Antiphospholipid Antibody Syndrome

• 28% of 178 non-SLE transplant recipients had APL antibodies that were assoc w/ 3-4 fold increased risk of arterial and venous thromboses

• HCV-positive renal transplant recipients with anticardiolipin antibodies appear to have a higher risk of TMA in the allograft

Therapy• Remains to be defined• Higher IgG APL antibody titers blamed for increased

incidence of thrombotic events• Aspirin for APL antibodies w/o thrombotic events• High-dose anticoagulation for APL syndrome (primary or

sec to SLE)• Uncertain role of immunosuppression• In pregnancy with APL syndrome:

– Heparin and low-dose aspirin = successful in several studies– Prednisone = no success

• In case of bleeding // thromboses despite adequate anticoagulation // pregnacy, some success reported with:– Plasmapheresis + corticosteroids– Other immunosuppressives– IVIG, Plaquenil (anecdotal)

Mixed Connective Tissue Disease

• Overlap: SLE/scleroderma/polymyositis• Very high ANA titer (often speckled)• ENA with anti-U1RNP antibodies• Glomerular lesions resemble the spectrum found in SLE

– Glomerular disease is the most common kidney lesion in MCTD– Up to 30% have mesangial deposits of IgG and C3– Focal proliferative GN with mesangial and subendothelial

deposits– Glomerular fibrinoid necrosis and crescent formation are rare

• Vascular lesions (when present) resemble those found in scleroderma

Primary systemic sclerosis

• Anti-centromere antibodies (96%) in pts with limited cutaneous scleroderma (including CREST syndrome) w/o renal disease– sensitivity is only 43% for cutaneous

scleroderma

• Presence of anti-centromere antibodies reduces the likelihood of developing renal complications

Primary systemic sclerosis

• Anti-Scl-70 antibodies > 90% positive predictive value for systemic sclerosis– Insensitive and not good for excluding

systemic sclerosis

• Presence of anti-Scl-70 antibodies is a predictor of likelihood of renal involvement or patient survival

Wegener Granulomatosis

• Systemic vasculitis

• Necrotizing glomerular lesions– The classic histopathologic finding is focal

segmental necrotizing and crescentic GN– Large number of crescents are more often

found in c-ANCA positive pts

Wegener Granulomatosis – Therapy

• The heterogeneity of vasculitis and differing approaches to classification have hindered the accumulation of evidence to direct therapy

• Most clinical trials have had sample sizes too small to allow conclusions to be made and treatment protocols have developed along empirical and, more recently, consensus lines

• Vasculitis occurring in the context of Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss angiitis and polyarteritis nodosa appears to respond in a similar way to therapy and it is probable that disease severity should determine the protocol rather than diagnostic subgroup

Wegener Granulomatosis – Therapy

• When threatened vital organ damage is present, early effective treatment will improve long-term outcome, as has been demonstrated for renal vasculitis, where renal function at remission determines long-term renal survival. In this regard, early diagnosis, before organ damage is sustained, is more important than therapeutic protocol

• The importance of balancing treatment efficacy with toxicity recurs in the existing literature and has inspired the use of protocols of graded intensity for progressively severe vasculitis. The CYCAZAREM protocols also appear to favor efficacy over toxicity, because the remission rate was very high yet treatment toxicity contributed to deaths in six and caused serious adverse effects in over one quarter

• In addition to the need for less toxic therapies overall, there is a more urgent requirement for the elderly to be regarded as a separate subgroup and appropriate protocols designed to offer a more favorable balance with less toxicity

Wegener Granulomatosis – Therapy

• The advent of newer immunosuppressives and biological agents targeting specific immune components offers exciting possibilities for the vasculitis specialist

• Unfortunately, experience with these drugs in vasculitis is usually delayed until they are licensed for a particular indication, typically transplantation or rheumatoid arthritis. If proven effective and safe, the expense of these agents will also require the design of cost–benefit strategies in vasculitis before they can be routinely recommended

Microscopic polyangiitis

• Systemic vasculitis

• Necrotizing glomerular lesions– The classic histopathologic finding is focal

segmental necrotizing and crescentic GN– Large number of crescents are more often

found in c-ANCA positive pts

Churg-Strauss Syndrome(aka. Allergic Granulomatosis)

• Rare systemic vasculitis– Only several hundred cases reported in the literature since the

first case in 1951 (? underrecognized)– Vasculitis, asthma, organ infiltration by eosinophils, and

peripheral eosinophilia• >50% have kidney involvement in autopsy series• Clinical renal disease described in 25-90%• Variety of lesions found on K. Bx’s from normal to severe

GN, vasculitis and interstitial inflammation– Necrotizing glomerular lesions are seen less often

• The classic histopathologic finding is focal segmental necrotizing GN, sometimes with small crescents

• In most cases the GN is mild, affects only several glomeruli and involves the tuft segmentally

– Least likely (among the pauci-imune GN’s) to be c-ANCA positive & to have large number of crescents

Temporal arteritis

• Renal manifestations = rare– Mild hematuria– Mild proteinuria– No renal failure

Takayasu Arteritis

• Obliterative arteritis of the main renal artery renovascular HTN

• Narrowing of the renal ostia due to abdominal aortitis renovascular HTN

• Mild hematuria• Mild proteinuria• No renal failure• High BUN/serum creatinine ratio• Mild mesangial proliferative GN (IgG, IgM, IgA,

C3, C4)

Anti-Endothelial Cell Antibodies (AECA)

• Detected in the serum of pts with renal disease caused by GN and thrombotic angiopathies

• Assay rarely used as diagnostic tool due to technical difficulty

• AECA can be directed against large vessel endothelial cells (Takayasu arteritis, Kawasaki disease) and to microvascular endothelium in HIT, TTP, Behcet, multiple sclerosis

Henoch-Schonlein Purpura

• Discussed under “Primary GN”

Anti-GBM Disease and Goodpasture Syndrome

• Discussed under “Primary GN”

Sjogren Syndrome

• Tubulointerstitial involvement– Distal RTA– Impaired concentrating ability– Hypercalciuria– PT defects (less often)– Bland UA– Mild elevations of serum creatinine– GN (rarely): hematuria, proteinuria, renal

insufficiency, NS, renal vasculitis (renal insufficiency and severe HTN)

Sarcoidois

• Interstitial nephritis (typically granulomatos)

• Nephrolithiasis

• Tubular fxn abnormalities

Mixed Cryoglobulinemia

• Assoc with a variety of:– Infections– Collagen-vascular diseases– Lymphoproliferative diseases

• Cryo– Type I single monoclonal Ig (Waldenstrom’s,

myeloma)– Type II (mixed) monoclonal Ig (IgM kappa in > 90%)

against polyclonal IgG (RF positive)– Type III (mixed) both polyclonal IgG & IgM

• Most types II & III have HCV infection

Inherited Disorders

• Hereditary Nephritis (Alport disease)

• Thin GBM Disease• Fabry Disease

(Angiokeratoma Corporis Diffusum Universale)

• Nail-Patella Syndrome(Hereditary Osteo-onychodysplasia)

Inherited Mutations of Podocyte Proteins

• Congenital NS of the Finnish Type (CNF)– Nephrin mutations

• AR Nephrotic Syndrome– Podocin mutations

Inherited Mutations of Podocyte Proteins

• AD Nephrotic Syndrome (FSGS)– Alpha-actinin-4 mutations

• Altered mechanical properties of the podocytes (impaired cytoskeletal fxn)

– Penetrance=high– Subnephrotic proteinuria and progressive

renal insufficiency

Glomerular Manifestations of Liver Disease

• Depends on the liver disease– Hepatitis B– Hepatitis C– Autoimmune Chronic Active Hepatitis– Cirrhosis

Glomerular Manifestations of Liver Disease

• Cirrhosis– Clinically manifest GN is rare– IgA deposition noted in more than 50% of pts

at both necropsy and bx (also found in some noncirrhotic kidney autopsy series)

– Kidney biopsy• Mesangial Sclerosis (cirrhotic glomerular sclerosis)• MPGN

– Henoch-Schonlein Purpura with RPGN (rarely)

Others

• Amyloidosis– Primary– Secondary

• Waldenstrom macroglobulinemia

• Sickle Cell Nephropathy